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Interactions between the pathogenic Neisseria (N. meningitidis and N. gonorrhoeae) and human cells


   School of Life Sciences

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  Dr K Woodridge  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Neisseria meningitidis (the meningococcus) is usually a harmless commensal bacterium which colonises the human nasopharynx. As far as is known humans are its only natural reservoir. For reasons that are poorly understood the organism occasionally invades the mucosa of the upper respiratory tract and invades the bloodstream, from where it can cause a systemic infection involving many organs. It is also capable of breaching the blood-brain barrier, which is normally impenetrable to most bacterial pathogens with the notable exceptions of Streptococcus pneumoniae (the pneumococcus) and Haemophilus influenzae, as well as the meningococcus.

The gonococcus (N. gonorrhoeae) is closely related to N. meningitidis but causes a very different spectrum of disease. Antibiotic resistance among circulating gonococcal isolates is now a major problem worldwide and some circulating isolates are now virtually untreatable with current antimicrobials. Thus there is a pressing need for new approaches to treatment and prevention of gonorrhoea, the disease caused by this important pathogen.

We are characterising the complex interplay between bacterial surface and secreted proteins of N. meningitidis and their human targets. This work is now being extended to N. gonorrhoeae.

We identified and characterised the specific interaction between the human laminin receptor and bacterial surface proteins as an essential pre-requisite for breaching the blood-brain barrier; we are currently characterising the cell signalling pathways that follow this interaction (Alqahtani et al., 2014). In addition, we have recently reported that the human Fibroblast growth factor receptor 1 is a target for the meningococcus and interaction between this receptor and the bacterium leads to invasion of human microvascular epithelial cells, which form the blood-brain barrier (Azimi, Wheldon, Oldfield, Ala'Aldeen, & Wooldridge, 2020).

Bacterial surface and secreted proteins are targeted to the cell surface via a number of different pathways, which might constitute targets for future therapeutics. We have recently demonstrated the role of chaperone proteins present within the periplasmic space (the space between the bacterial inner and outer membranes) in the translocation of important virulence factors to the bacterial surface. Furthermore, we have shown that variant signal peptides found in the important surface protein virulence factor Factor H-binding protein affects its surface localisation, with important implications for susceptibility to current vaccines deployed against Group B meningococci (da Silva et al., 2019).

We are currently further investigating these aspects of meningococcal and gonococcal pathogenesis. The student would work as part of a team investigating aspects of this host-pathogen interaction. The student would work in a containment level 2 laboratory and will be supervised by a team of 2 academics with extensive experience working with N. meningitidis and N. gonorrhoeae. The student will learn a variety of techniques in basic microbiology, molecular biology, advanced microscopy and protein purification and analysis.

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.


References

Alqahtani, F., Mahdavi, J., Wheldon, L. M., Vassey, M., Pirinccioglu, N., Royer, P. J., . . .
Ala'Aldeen, D. A. (2014). Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis. Open Biol, 4(10). doi:10.1098/rsob.140053
Azimi, S., Wheldon, L. M., Oldfield, N. J., Ala'Aldeen, D. A. A., & Wooldridge, K. G. (2020). A role for fibroblast growth factor receptor 1 in the pathogenesis of Neisseria meningitidis.
Microb Pathog, 149, 104534. doi:10.1016/j.micpath.2020.104534
da Silva, R. A. G., Karlyshev, A. V., Oldfield, N. J., Wooldridge, K. G., Bayliss, C. D., Ryan, A., & Griffin, R. (2019). Variant Signal Peptides of Vaccine Antigen, FHbp, Impair Processing Affecting Surface Localization and Antibody-Mediated Killing in Most Meningococcal Isolates. Front Microbiol, 10, 2847. doi:10.3389/fmicb.2019.02847

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